16alpha, 17alpha-cyclic esters of steroids of the pregnene series



7 3,049,541 Patented Aug. 14, 1962 Fine 3,049,549 160:,17zx-CYCLIC ESTERS F STEROIDS OF THE PREGNENE SERIES Josef Fried, Princeton, NJ assignor to 01m Mathreson Chemical Corporation, New York, N.Y., a corporation of Virginia N0 Drawing. Filed May 2, 1960, Ser. No. 25,866 18 Claims. (Cl. 260-23955) This invention relates to, and has for its object, the provision of a method for preparing physiologically active steroids and to the physiologically active stroids produced thereby.

The steroids of this invention include the 16a,l7tzcyclosulfite and l6u,l7a-cyclosulr"ate esters of 16o,170cdihydroxy steroids of the pre nene series unsubstituted in the C-ring, which series includes, inter alia, compounds having either a pregnene, a pregnadiene, or a pregnatriene nucleus. More particularly, this invention includes 16cc, l7a-cyclosulfite and 1641,1711 cyclosulrate esters of preg nenes represented by the following general formula:

wherein the 1,2 and/or 6,7 positions are saturated or double bonded; Q is hydrogen or methyl; R is hydrogen, lower alkyl (especially methyl) or halo in either the alpha or beta position; 11 is one or two; and Z is hydrogen, halogen (especially chloro and fluoro), hydroxy or the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms, such as an alkanoic acid especially the lower alkanoic acids (cg, acetic acid, propionic acid, and hexanoic acid), a monocyclic aromatic car-boxylic acid (e.g., benzoic acid, and o,rn and p-toluic acids), a monocyclic lower aralkanoic acid (e.g., phenylacetic acid and fl-phenylpropionic acid), a lower alkenoic acid, a lower cycloalkanoic acid, or a lower cycloalkenoic acid.

Among the compounds of this invention there may be mentioned the l6u,l7a-cyclosulfate and l6a,l7a-cyclosultite esters of C-ring unsubstituted 16a,17rz-(lll1yClI'OXy progesterones, which class of esters includes the followmg:

(I) The l6e,17a-cyclosulfate and 160:,170: cyclosulfite ester of 6-halogenated 16a,l7a-dihydroxyprogesterones, especially the 16-.t,l7ot-cyclosulfate and 160:,l7a-CYClOSUlfite esters of S-fluoro and 6-chloro-l6a,l7a-dihydroxyprogesterones, such as the l6a,l7a-cyclosulfate and l6a,17acyclosulfite esters of 6u-fiuoro-l6tx,l7a-dihydroxyprogesterone, the l6a,l7ot-cyclosulfate and l6oc,17o:-CyClOSLllfite esters or" 6,8,21-dichloro-l6a,l7a-dihydroxyprogesterone, the l6e,l7a-cyclosulfate and l6a,l7a-cyclosulfite esters of 6,8-fiuoro-l6a,l7u-dihydroxy-l-dehydroprogesterone, and the l6a,l7a-cyclosulfate and 1604,17oc-CYC- sulfite esters of 6ot-fluoro-l6e,l7a,2l-trihydroxyprogesterone and 21-esters thereof (e.g. the Zl-acetate);

(H) The l6a,17a-cyclosulfate and l6u,l7u-cyclosulfite esters of 6-loWer alkylated-l6a,l7ct-dihydroxyprogesterones, especially the 16a,l7a-cyclosulfate and l6a,17acyclosulfite esters of 6-methyl(or ethyl)-l6tx,17a-dihydroxyprogesterones, such as the 16a,l7a-cyclosu1fate and 16:4,17cc-CYC10Slllfit6 esters of 6u-methyl16a,l7a-dihydroxyprogesterone, the l6a,l7a-cyclosul-fate, and 16oc,l7a cyclosulfite esters of 6B-n1ethyl-l6a,17adihydr0xyprogesterone, the l6a,l7a-cyclosulfate and l6c,l7ocCyClOSlllfite esters of 6B-ethyl-l6a,17a-dihydroxyprogesterone, the l6a,l7a-cyclosulfate and :,l7ot-CYC1OSIllfii6 esters of 6aethyl-l6o,l7a-dihydroxyprogesterone, the 160:,l7ot-CYC10- sulfate and l6a,l7ca-CyClOSU.lfite esters of 6a-methyl-2lfluorol 60:, l 7a-dihydroxyprogesterone, the 1600,1704-CY- closulfate and l6u,l7tx-cyclosulfite esters of 6amethyll6tx,l7a-dihydroxy-l-dehydroprogesterone, and the 160:, l7a-cyclosulfate and 16a,17a-cyclosulfite esters of 6amethyl- 1 6a, 1 704,2 1 -trihydroxyprogesterone and 2 l -esters thereof (e.g., the ZI-acetate);

(ill) The l6tz,l7a-cyclosulfate and l6m,l7a-cyclosulfite esters of 6-clehydro-l6oz,17cc-dihydroxyprogesterones such as the l6a,l7a-cyclosulfate and l6a,l7a-cyclosulfite esters of 6-dehydro-16u,17a-dihydroxyprogesterone, the 160:,17nc-Cf/Cl0511lf21i6 and 1606,170tCYClOSHlfit6 esters of A1145 pregnatriene 16a,l7oc diol 3,20 dione, the l6c ,l7a-cyclosulfate and l6a,l7a-cyciosulfite esters of 6- dehydro-16u,17a,2l-trihydroxyprogesterone and 2l-esters thereof (e.g., the 2l-acetate) and the l6a,l7a-cyclosulfate and l6a,l7tx-cyclosulfite esters of 6-dehydro-l6fi-methyl- 16a, 1 7a-dihydroxyprogesterone; and

(1V The 16u,l7a-cyclosulfate and l6a,17a-CyClOSulfite esters of 6-unsubstitu-ted- 1 6a, 1 7a-dihydroxyprogesterones, such as the 16a,17a-cyclosulfate and l6a,l7a-cyclosulfite esters of 16a,l7a-dihydroxyprogesterone, the l6a,l7acyclosulfate and 16a,l7u-cyclosulfite esters of 2l-fluoro- 16a,17a-dihydroxyprogesterone, the 16a,l7a-cyclosulfate and l6cz,l7a-cyclosulfite esters of 16m,170L-CllhydTOXy-1- dehydroprogesterone, the l6a,l7u-cyclosulfate and 16a, l'l'oc-CYClOSulfitB esters of l60:,17a,2l-trihydroxyprogesterone and Zl-esters thereof (e.g. the Zl-acetate), and the 16a,l7a-cyclosulfate and 16cc,17oc-CyClOS1llfi6 esters of 16,8-methyl-16a,17a-dihydroxyprogesterone.

The compounds of this invention can be prepared by a process of this invention which comprises reacting a streoid of the general formula:

wherein the 1,2 and/or the 6,7 positions are saturated or double bonded; R and Q are as hereinbefore defined and Z is hydrogen, halogen (e.g. chloro or fluoro) or an acyloxy radical of a hydrocarbon carboxylic acid of the group hereinbefore defined, With either thionyl chloride or sulfuryl chloride in the presence of an hydrogen chlo! ride accept-or such as an organic nitrogen base (e.g., pyridine, collidine, triethanolamine and quinoline), and recovering the 16,17- cyclic ester thus formed. The reaction is preferably carried out at temperatures below 0 C. by treating a solution or suspension of the steroid in the basic medium with either thionyl chloride or sulfuryl chloride and then recovering the product by conventional procedures.

The steroidal starting materials for preparation of the compounds of this invention are, generally, C-ring unsubstituted derivatives of 16,17-dihydroxyprogesterones.

Among the suitable steroidal starting materials there may be mentioned inter alia:

(I) 6 halogenated l6a,l7ot dihydroxyprogesterones, especially 6-fluoro and 6-chloro-dihydroxyprogesterones, such as 6a-fluoro-16a,17a-dihydroxyprogesterone, and 21- esters of 60a flllO1'0-16a,l7 :,21-t1il1Yd1'0XYPI0g8StG1'OH6 (e.g. the 2l-acetate);

(II) 6-lower alkylated-16at,17 a-dihydroxyprogesterones especially G-methyl (or ethyl)-16a,l7a-dihydroxyprogesterones, such as 6u-methyl-l6a,l7a-dihydroxyprogesterone, 6a ethyl 160:,17 0c dihydroxyprogesterone, 6ozmethyl-l6a,17u-l-dehydrodihydroxy-progesterone, and 21- esters of 6amethyl-16a,17u,21-trihydroxyprogesterone (e.g., the 21-acetate); and

(III) 6 unsubstituted-16a,17a-dihydroxyprogesterones, such as 16a,17a-dihydroxyprogesterone, 16u,17a-dihydroxy-l-dehydroprogesterone, 21-esters of 16a,l7a,21-t1ihydroxyprogesterone (e.g., the 21-acetate) and 16pmethyl-16cc,l7a-dihyd-roxyprogesterone.

Alternatively, the compounds of Formula I wherein n is two may be prepared by the oxidation of the corresponding compound of Formula I wherein n is one with an oxidizing agent such as calcium permanganate.

Where a particular l-dehydro steroid is desired and only the corresponding 1,2-saturated derivative is available, the latter can be converted to the former by 1,2-dehydrogenation with Bacterium cyclooxydans in accordance with the method set out in Example 1 of U.S. Patent No. 2,822,318.

The 6-halo-l6a,l7a-dihydroxyprogesterones used herein are described in copending application Serial No. 7,521, filed February 9, 1960. The 6-methyl-16a,17a-dihydroxyprogesterone starting materials used herein are described in application Serial No. 830,467, filed July 30, 1959. p The 2l-acyloxy-l6,17-esters of this invention can be prepared by the alternative process which comprises treating the 16a,17a,2l-trihydroxyprogesterone starting material with acetone and perchloric acid followed by treatment with an acid anhydride corresponding to the acyloxy radical desired to yield the 16a,l7a-acetonide-2l-acylate which is treated with formic acid to hydrolyze the 16,17- ketal group. The l6a,17oc,21-11IihYdl'OXY-2l-3CY1EI'I6 derivative is converted to its 16,17-cyclic ester by the hereinbefore described treatment with thionyl or sulfuryl chloride.

The 21-halogenated esters of this invention can alternatively be prepared by treating the corresponding 16a, 17a,21-trihydroxyprogesterone with acetone and perchloric acid to yield the corresponding 16,17-acetonide and treating the latter with an organic sulfonyl halide such as mesyl chloride or tosyl chloride to form the 21-sulfonyloxy-16,17-:acetonide derivative which is then treated with an alkali metal halide such as lithium chloride, lithium bromide, sodium iodine or potassium bifiuoride to yield the corresponding ill-chloride, bromide, iodide, or fluo ride, respectively. The 21-halol6,l7-acetonides are deacetonated by hydrolysis with an acid (e.g. formic acid) and then treated with thionyl chloride or sulfuryl chloride as hereinbefore described, to yield the desired esters.

The 6-dehydro-l6,17-esters of this invention may be prepared by reacting the corresponding 6,7-saturated starting material with a 6,7-dehydrogenating agent (e.g., chloranil in a mixture of ethyl acetate and acetic acid) and separating the 6-dehydro derivative thus formed.

The l6 3-methly-16,17-esters of this invention are prepared by ketalizing a l6-methyl-A -pregnadiene-3-ol- 20-one with a lower alkylene glycol in the presence of an acid catalyst (e.g. toluenesulfonic acid), treating the resulting 20-cthylene ketal derivative with an oxidizing agent such as aluminum tertiary butoxide in cyclohexanone to form the corresponding A -3 -one which is then converted to l6fi-methyl-l6a;l7a-dihydroxyprogesterone 20- ethylene ketal by treatment with osmium tetroxide followed by a reducing agent such as hydrogen sulfite. The dihydroxy compound is converted to its cyclic sulfite or sulfate ester by a two step process involving either hydrolysis of the 20-ketal group with an acid (e.g., sulfuric acid) and then esterification at the 16,17-posi-tions or first esten'fication at the 16,17-positions and then hydrolysis of the ketal radical with an acid (e.g., perchloric acid).

The 6B-methyl and 6B-halo-cyclic esters of this invention are prepared by treating a 6fi-methylpregnane-5a,l6u, 17e-triol-3,20-dione (preparedas disclosed in my copending application Serial No. 830,467, filed July 30, 1959) or the corresponding 6 3-halo-tn'ol (described in the same application) with either thionyl chloride or sulfuryl chloride in an organic base as hereinbefore disclosed to simultaneously esterify the 16,17-position and dehydrate the 4,5a-position thereby yielding 6B-methyl- 16a,17u-dihydroxyprogesterone-16a,17a-cyc1ic ester or the 613 halo-16a,l7a-dihydroxyprogesterone 16a,17a-cyclic ester, respectively.

If a 2l-acyloxy steroid is employed as the starting material and the corresponding 21-hydroxy steroid is desired as the final product, the 2l-acyloxyl6a,17a-dihydroxyprogesterone 16u,l7a-cyclic ester product is hydrolyzed as by treatment with an alkali metal carbonate (e.g. potassium carbonate) to yield the desired free 21-hydroxy final product. Alternatively, the 21-acyloxy products of this invention may be converted to the corresponding 11B- hydroXy-Zl-acyloxy-derivatives by known methods such as by subjecting the 21-acyloxy-1l-desoxy-starflng material to microbiological oxidation by the enzymes of Cunninghamella blakesleeana as disclosed in Steroids, Fieser, p. 673 (1959).

The compounds of this invention as represented' by Formula II are physiologically active substances which possess progestational and anti-uterotrophic activity and hence can be used in lieu of known progestational agents, such as progesterone, in the treatment of diseases and conditions such as habitual or threatened abortion, amenorrhea, metropathic hemorrhagica, dysmenorrhea, inadequate corpus luteum function and premenstrual tension, being formulated for such administration in the usual perorally or parenterally acceptable formulations.

The following examples illustrate, without limiting this invention (all temperatures being in degrees centigrade):

EXAMPLE 1 1600,] 7 a-Dihydroxyprogesterone 1 6 11,1 7 a-Sulfite To a solution of 1.5 g. of l6a,l7ot-dihydroxyprogesterone in 20 ml. of anhydrous pyridine is added at -l5 with stirring 3 ml. of pure thionyl chloride. The reaction is allowed to proceed at 15 for 3 minutes, after which time ice water is added slowly causing crystallization of the resulting sulfite ester. The crystals are filtered, washed thoroughly with water and dried in vacuo. The

' dried product melts at about 268-273" and weighs about 1.45 g. To obtain analytically pure material the above product is dissolved in 12 ml. of chloroform and 4 ml. of benzene and chromatographed on 30 g. of Woelm neutral alumina. Elution of the column with 400 ml. of a mixture of three parts of chloroform and one part of benzene gives material, which upon one crystallization from acetone, furnishes analytically pure l6a,l7a-dihydroxyprogesterone 16a,l7a-sulfite having the following properties: M.P. about 278-279"; [a] +l82 (c., 1.15 in chlf.); 239 my (e=l6,200); 1232 5.81, 5.98, 6.20 and 8.29

Analysis.--Calcd for C H O S (392.48): C, 64.27; H, 7.19; S, 8.17. Found: C, 64.26; H, 7.07; S, 8.23.

16a,l7oz-dihydroxyprogesterone 16a,17a-sulfite possesses twice the activity of progesterone in the parenteral Clauberg assay.

EXAMPLE 2 a,] 7a-Dihydr0xy-1 -Dehydroprogester0ne 16u,17a- Sulfite To a solution of 1.5 g. of 16a,17a-dihydroxy-1-dehydroyield the product 16a,17a-dihydroxy-l-dehydroprogesterone 16oz, 17a-sulfite.

EXAMPLE 3 16a,]7:1,21-Trihydr0xyprogester0ne 16,1 7-Sztlfite-2Z Acetate Following the procedure of Example 1, 16a,17a,21-trihydroxyprogesterone 2l-acetate (prepared by treating 100 mg. of 16u-hydroxycortexolone with acetone and 0.01 ml. of 70% perchloric acid to yield the 16,17-acetonide derivative of 16a-hydroxycortexolone which is first transformed to its 21-acetate by treatment with pyridine and acetic anhydride and then to the desired 16a-hydroxycortexolone 21-acetate by hydrolysis of the 16,17-ketal group with 60% aqueous formic acid) is treated with thionyl chloride to yield a crystalline product which is separated from the reaction mixture and then chromatographed on neutral alumina using chloroform-benzene as the eluant to yield the product 16a,1711,21-trihydroxyprogesterone 16a,17a-sulfite 21-acetate.

EXAMPLE 4 1 6 fi-M ethyl-1 6 05,1 7 a-Dihydroxyprogesterone ]6a,17a- Sulflte (A) Preparation of A -16-methylpregnadiene-3fi-ol- 20-0ne-20-ethylene ketaZ.-A mixture of 3 g. of A -16- methylpregnadiene-3B-ol-20-one, 9 ml. of ethylene glycol and 112 m1. of benzene is heated at reflux with stirring with the aid of a Dean-Stark separator. When 20 ml. of benzene has distilled, 186 mg. of toluenesulfonic acid monohydrate is added to the mixture and the reaction is allowed to proceed with stirring for 16 hours at reflux temperature. After cooling, the mixture is neutralized by the addition of sodium bicarbonate solution followed by the addition of water. The layers are separated, the benzene extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue after recrystallization from acetone furnishes the pure ketal of the following properties: M.P. about 168-169"; [u] 82 (c., 1.25 inchlf).

Analysis.-Calcd for C l-1 (372.53): C, 77.34; H, 9.74. Found: C, 77.22; H, 9.40.

(B) Preparation of A -16-methylpregnadiene-3,20-dione-ZO-ethylene ketals.-A solution of 2.5 g. of A -16- methylpregnadiene-3/i-ol-20-one 20-ethylene ketal in a mixture of 90 ml. of xylene and 30 ml. of freshly distilled cyclohexanone is distilled until ml. of distillate have been collected. To this solution is added 2.5 g. of aluminum tertiary 'butoxide and the resulting solution is refluxed for 50 minutes. Water is added and after separation of the layers the aqueous phase is extracted thoroughly with chloroform. The combined xylene and chloroform extracts are dried over sodium sulfate and the solvents and the cyclohexanone removed in high vacuum. The remaining residue is taken up in hexane and chilled, upon which crystallization occurs. Yield: about 1.69 g. The analytically pure material obtained after recrystallization from acetone, exhibits the following properties: M.P. about 175177; [a] [-61 (c. 1.1 in chlf.);

N53; 240 m (e=l5,700); A232 5.99, 6.12 and 621 Analysis.Calcd for C H O (370.51): C, 77.80; H, 9.25. Found: C, 77.76; H, 9.38.

(C) Preparation of 16,8-metlzyl-16a,Z7a-dihydr0xyprogesterone ZO-ethylene ketal.To a solution of 555 mg. of A -l6-methylpregnadiene-3,20-dione ZO-ethylene ketal 6 in 45 ml. of benzene and 2.25 ml. of pyridine is added 438 mg. of osmium tetroxide. The vessel containing the reaction mixture is stored in total darkness at room temperature for 21 hours. ml. of dioxane is then added and the resulting solution saturated with hydrogen sulfide for 7 minutes. The osmium precipitate is centrifuged off and the clear solution added to chloroform and water. The organic layer is washed several times with water, dried over sodium sulfate and evaporated to dryness in vacuo. There remains a crystalline residue which after recrystallization from acetone-hexane furnishes pure 16 methyl-l6a,17a-dihydroxyprogesterone ZO-ethylene ketal of the following properties: M.P. about 186-187 and about 172-174 (polymorphic modificaions); [a] +74 (c., 1.38 in chlf.); +54 (c., 1.24 in methanol);

tag- 240 m $16,100 m 2.99, 6.03 and 6.23,.

Analysis.-Calcd for C H O (404.53): C, 71.25; H, 8.97. Found: C, 70.88; H, 9.19.

(D) Preparation of 16B-methyl-16a,17oc-dihydr0xyprogesterone :,17cc-Sltlfit6 20-ethylene ketal.To a solution of 200 mg. of l6fi-methyl-l6a,17u-dihydroxyprogesterone 20-ethylene ketal in 6 ml. of pyridine is added at '15 with stirring 0.2 ml. of thionyl chloride and the reaction is allowed to proceed at that temperature for 3 minutes. Ice water is then added and the resulting crystals removed by filtration and washed well with water. Recrystallization of this material (about 215 mg.) from chloroform-ethanol furnishes about mg. of pure 16B- methyl-16a,17a-dihydroxyprogesterone 160;,17a-S111flt6 20- ethylene ketal of the following properties: M.P. about 225-226; [a] +8-1 (c., 1.03 in chlf.);

Analysis.-Calcd for C I-1 0 8 (450.57): C, 63.94; H, 7.60. Found: C, 63.85; H, 7.88.

(E) Preparation of 16,8-methyl-J6a,I7oc-dihydr0xyprogesterone 16a,17u-sulfite.To a solution of 100 mg. of 1 6fi-methyl-l 60c, 17oc-dihydroxyprogesterone 1 6u,17a-sulfite 20-ethylene ketal in 12 ml. of methanol is added 1.04 ml. of 70% perchloric acid and the mixture is stirred at room temperature for 16 hours. Water is added and the solution is neutralized with sodium bicarbonate. The bulk of the methanol is removed in vacuo and the resulting suspension extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue after crystallization from methanol yields 16,B-methyl-16a,-17 xdihydroxyprogesterone 16u,17a-sulfite of the following properties: M.P. about 178-179 and about 196-203 (polymorphic modifications); [a] +lZ6 (c., .82 in chlf.);

A312,; 239 m (e=16,400);

8.20-8.30a Analy'sis.Calcd for C H O S (406.46): C, 64.99;

H, 7.43; S, 7.90. Found: C, 64.38; H, 7.78; S, 7.85.

(F) Alternative preparation of 16fi-methyl-16aJ7a-dihydroxyprogesterone 16a,17ot-sulfite.A solution of 78 mg. of 16fl-methyl-16a,17oc-dihydroxyprogesterone 20- ethylene ketal in 23 ml. of methanol and .78 ml. of 8% sulfuric acid is hea-ted under reflux for 45 minutes. The mixture is cooled, neutralized with dilute sodium bicarbonate and after removal of the bulk of the methanol in vacuo extracted with chloroform. The chloroform extract is washed With Water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual material after recrystallization from acetone-hexane furnishes pure 16,8-methyl-16a,17a-dihydroxyprogesterone of the following properties: M.P. about 258-26l; [u] +44 (c., .39 in chlf.);

ANuiol A319,; 239 mp (6=17,200); 2.95, 6.05 and 6.21 1

Analysis.Calcd for (3 1-1 0 (360.48): C, 73.30; H, 8.95. Found: C, 73.32; H, 8.92.

Reaction of 16 8-methyl-16a,17a-dihydroxyprogesterone N '01 Nail.

5.83, 5.90, 0.20, and

with thionyl chloride in pyridine at -l5 as described in part D furnishes the 16,17-suliite identical with the product obtained in part E.

EXAMPLE 5 21 -Flur0-16a,1 7a-Dihydroxyprogesterone 160a,] 7a- Sulfite 16a,170:,2l-trihydroxyprogesterone is treated with acetone and perchloric acid to form 16a,l7a,Zl-trihydroxyprogesterone 16,17-acetonide which is then treated with mesyl chloride under anhydrous conditions at a temperature of 0. After two hours, water is added and the precipitated ZI-mesylate is removed by filtration, washed thoroughly, dried in vacuo and recrystallized from acetone-hexane. The crystalline mesylate is dissolved in ethylene glycol and treated with potassium biiiuoride at reflux temperature for forty hours after which the reaction mixture is diluted with water and the crystals filtered ofi, dried in vacuo and then recrystallized from acetonehexane to yield the product 2l-fluoro-l6a,17a-dihydroxyprogesterone 16a,l7u-acetonide.

The 16,17-acetonide is deactonated by treatment with 60% formic acid at 100 to yield 21-fluoro-l6a,l7-dihydroxyprogesterone which is converted by treatment with thionyl chloride and pyridine to the product ZI-fluoro- 16a,17wdihydroxyprogesterone l6a,17a-sulfite.

Similarly, except for the introduction of the methyl group into the corresponding 21-chloro, 21-bromo and 21- iodo derivatives (prepared by treating the 21-mesylate with lithium chloride, lithium bromide and sodium iodide respectively) there are obtained 2lChl0I'O-16oc,17oc-dihydroxyprogesterone 16a,l7a-sulfite, 21bI'OmO-16or.,l7oc-dihydroxyprogesterone 16a,17a-sulfite and 2l-iodo-l6a,l7adihydroxyprogesterones l6a,17u-sulfite, respectively.

EXAMPLE 6 1611,] 7a-Dihydroxyprogesterone 1 6 0a,] War-Sulfate To a solution of 200 mg. of l6u,l7a-dihydroxyprogesterone in 60 ml. of pyridine is added at '1S, 0.2 ml. of redistilled sulfuryl chloride. The reaction is allowed to proceed at 10 to l for 15 minutes after which time ice Water is added and the mixture is extracted with chloroform. The chloroform extract is washed with l N sul- (furic acid, water, dilute sodium bicarbonate and again with water, dried over sodiumsulfate and the solvent evaporated in vacuo. The crystalline residue, after recrystallization from chloroform-ethanol, furnishes about 150 mg. of pure 16a,l7u-dihydroxyprogesterone 16a,17or.- sulfate of the following properties: M.P. about 271-473"; [u] +155 (c., .99 in chlf.);

Wig- 238 mp. (e 14,400) REE? 5.79, 5.99, 6.20, 7.20, 8.29;].

Analysis.-Calcd for C H O S (408.49): C, 61.75; H, 6.90; S, 7.87. Found: C, 61.74; H, 6.97; S, 7.96.

EXAMPLE 7 160a,] 7a-Dihydr0xypr0gester0ne 1 6 11,1 7a-Sulfate To a solution of 1 g. of 16a,l7oc-dihYd10XYPI'Og6S'E6IOI16 16u,17u-sulfite in 25 ml. of glacial acetic acid is added slowly with stirring and cooling to %5", a filtered solution of 3 g. of calcium permanganate in 6 ml of water. When the reaction is completed as indicated by the permanent pink color of the solution, the mixture is poured into ice water and extracted with chloroform. The chloroform extract is washed with water, sodium bicarbonate solution, the last washes containing some sodium sulfite to remove excess permanganate, and water, and the chloroform extract dried over sodium sulfate. The solvent is removed in vacuo and the residual 16cz,17 xdihydroxyprogesterone 16oz,l7oc-S11lfate is recrystallized from chloroform-ethanol.

EXAMPLE 8 1 6 05,1 7a-Dihydr0xy-1-Dehydr0pr0gester0ne 1611,] 7a-Sulfate To a solution of Y200 mg. of 16a,17u-dihydroxy-'1- dehydroprogesterone in 60 ml. of pyridine is added at l5, 0.2 ml. of redistilled sulfuryl chloride. The reaction is allowed to proceed at -l0 to -15 for fifteen minutes after which time ice water is added and the mixture is extracted with chloroform. The chloroform extract is washed with 1 N sulfuric acid, water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and the solvent evaporated in vacuo. The crystalline residue after recrystallization from chloroform-ethanol furnishes substantially pure l6a,17u-dihydroxy-l-dehydroprogesterone l6a,l7a-sulfate.

EXAMPLE 9 1 6 0a,] 704,21 -Trihydroxy progesterone 16ml 7a-Sulfate 21 -Acetate EXAMPLE 10 1 6 fi-M ethy l-1 6 a, 1 70c-D ihydroxy progesterone 16,17a-Sulfate Following the procedure of Example 6, redistilled sulfuryl chloride is added to 16B-methyl-l6a,17a-dihydroxyprogesterone in pyridine at a temperature of 15. The reaction is allowed to proceed at l0 to 15 for 15 minutes after which time ice water is added and the mixture is extracted with chloroform. The chloroform extract is washed with 1 N sulfuric acid, water, dilute sodium bicarbonate and again with water, dried over sodium'sulfat'e and the solvent evaporated in vacuo leaving a crystalline residue which is recrystallized from chloroform-ethanol to yield the product 16fi-methyl- 16a,17a-dihydroxyprogesterone :,17a-S1llf2tt6. I

EXAMPLE 11 from chloroform-ethanol furnishes pure 6oc-fil101'0-l6a,-

l7a-dihydroxyprogesterone sulfite of the following properties: M.P. about 296298 (dec.); [a] +171 (c.,

1.0 in chlf.); p

rag 234 m, (e: 12,600) xggis 5.81, 5.95, 6.17 and 8.28,; Analyst's.Calcd for c n o rs (410.48): 0, 61.45;

H, 6.63; S, 7.81. Found: C, 61.45; H, 6.74; S, 7.91.

Following the procedure of Example 11, 6a-chloro- 16u,17a-dihydroxyprogesterone (prepared by treating 16a,17wepoxy-progesterone in dioxane with ethyl orthoformate in ethanol and sulfuric acid to form 3-ethoxy- 16a,17aepoxy-A regnadiene-ZO-one which is treated in solution with dioxane, with N-chlorosuccinimide and a sodium acetate-acetic acid buffer followed by dilution with water. The resulting 6B-chloro-16a,17c-epoxyprogesterone dissolved in acetic acid, is treated with 33% HBr to yield 6a-chloro-16B-bromo-A -pregnene-17a-ol- 3,20-dione. The latter is converted to its 17u-acetoxy derivative by treatment with acetic anhydride in 70% perchloric acid and this product is treated With sodium acetate in acetic acid to yield 6aCl1lOrOl6cc,17a-dihydroxyprogesterone Mot-acetate, which is finally treated with methanolic potassium carbonate to yield the desired 6CL-Ch1OI'O-16d,17 a-dihydroxyprogesterone) is treated with tionyl chloride to yield the product 6u-Cl1lO1Ol6o,17adihydroxyprogesterone, 16a,17tz-sulfite.

EXAMPLE 13 6c.'.-flUO1O-l6zz,17oc dihydroxyprogesterone 16,17-sulfite is microbiologically 1,2-dehydrogenated in accordance with the procedure of Example 1 of U.S. Patent No. 2,822,318 to yield the product 6a-fluoro-1*6a,17a-dihydroxy-l-dehydroprogesterone 16a,17u-sulfite.

(A) Preparation of 6fi-flu0ropregnane-5oz,16a,17atril-3,20-di0ne 16a,17a-sulfite.-To a solution of 150 mg. of 6fl-fluoropregnane-5a,16a,17u-triol-3,20-dione (prepared as described in Serial No. 859,840, filed December 16, 1959) in ml. of dry pyridine is added 20 0.3 ml. of thionyl chloride. After 3 minutes at -20 ice water is added and the mixture extracted with chloroform. The chloroform extract is Washed with 2 N hydrochloric acid, water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and the solvent removed in vacuo. The crude residue (about 115 mg.) is dissolved in 5 ml. of chloroform and ml. of benzene and chromatographed on 2.5 g. of neutral alumina. Elution with 150 ml. of a mixture of five parts of benzene and one part of chloroform furnishes about 49 mg. of crude 6,B-fluoropregnane-5a,l6a,17a-triol-3,20- dione 160:,l7oz-Slllfit8 which after two crystallizations from acetone-hexane has the following properties: M.P. about 29029l, no selective absorption at 235mg;

AW 2.97, shoulder at 5.82, 5- and max.

(B) Preparation of 6B-flu0r0-16oc,17oc-dihydroxypr0- gesZerOne 16a,]7a-Sl[lfif.T0 a solution of 150 mg. of 613- fiuoropregnane-5a,16a,17a-triol-3,20-dione 16oc,170c-Slllfit in 6 ml of dry pyridine is added at 0 0.6 ml. of thionyl chloride. The mixture is allowed to stand at 0 for 30 minutes, after which time ice is added and the mixture extracted with chloroform. The chloroform extract is washed with 2 N hydrochloric acid, water, dilute sodium bicarbonate and again with Water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue (about 56 mg.) is dissolved in a mixture of 5 ml. of chloroform and 25 ml. of benzene and poured through a column of 1 g. of neutral alumina. The eflluent (25 ml.) furnishes about 10 mg. of crystalline material which after recrystallization from acetone-hexane represents pure 6fi-fluoro-16a,17a-dihydroxyi=0 progesterone 16u,17a-sulfite having the following properties: M.P. about 235238; [a] (c., .49 in chlf.);

x 1 232 th ($13,000) Analysis.Calcd for C H O FS (410) C, 61.44;

H, 6.63. Found: C, 60.68; H, 6.50.

EXAMPLE 15 6d-Fllt0i'0-1 6a,] 7a-Dilzydroxyprogesterone 16a,17oc- Sulfate To a solution of 95 mg. of 6a-fluoro-16a,17a-dihydroxyprogesterone in 3 ml. of pyridine is added at 15 0.1 ml. of sulfuryl chloride. The reaction is allowed to proceed for 15 minutes at 15, after which time ice water is added and the mixture taken up in chloroform. The resulting chloroform extract is washed With dilute sufuric acid, water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and the solvents removed in vacuo. The resulting crystalline residue (about 102 mg.) after recrystallization from chloroformethanol furnishes about 60 mg. of pure 6ocfluOIO-16oc,17adihydroxyprogesterone-16a,17a-sulfate of the following properties: MP. about 272 (dec.); [a] .+141 (c., 1.17 in chlf.);

A215,; 233 mu (e=l1,400);

Analysis.-Calcd for C H O ES (426.48): C. 59.15, H, 6.38; S, 7.51. Found: C, 58.94, H, 6.26; S, 7.69.

EXAMPLE 16 6 fl-F luoro-J 6 04,1 7 a-Dihydroxyprogesterone 160:,17oc- Sulfate Following the procedure of Example 7, 6B-fiuoro-16a, 17a-dihydroxyprogesterone 16a,17u-sulfite is treated with calcium permanganate, the reaction mixture extracted and the extract dried and then recrystallized to yield the product 6/3-fiuoro-161x,17a-dihydroxyprogesterone 16a, l7oz-SUlf3i6.

max.

5.78, 5.96, 6.16, 7.20 and XAMPLE l7 6 -Deh ya'ro-I 6 41,] 7 a-Dihydroxyprogesterone 16a,1 7a- Sulfite A solution of 250 mg. of 16a,17a-dihydroxyprogesterone l6u,l7a-Sulfite and 500 mg. of recrystallized chloranil is heated under reflux in a mixture of 10 ml. of ethyl acetate and 2 ml. of glacial acetic acid for 20 hours. The mixture is cooled, poured into Water and the layers separated. After additional extraction of the aqueous layer with ethyl acetate, the ethyl acetate extract is washed with 1 N sodium hydroxide solution until the aqueous layer became colorless (7 times). The ethyl acetate extract is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crude residue, which amounts to about 200 mg. is dissolved in benzene and chromatographed on 6 g. of neutral alumina. Elution of the column with 200 ml. of benzene containing 5% chloroform, furnishes about mg. of the crystalline sulfite ester which is analytically pure after recrystallization from acetone-hexane. The purse product has the following properties: M.P. about 229230; [u] ,+149 (.97 in chlf.);

kfllfg 232 mu (e=26,000); A232 5.84, 6.05, 6.19, 6.32 and Analysis.Calcd for C H O S (390.46): C, 64.58; H, 6.71; S, 8.22. Found: C, 64.51; H, 6.64; S, 8.17.

EXAMPLE 18 The product of Example 17 is miscrobiologically dehydrogenated with Bacterium cyclooxydans in accordance with the procedure of Example 1 of US. Patent No.

2,822,318 to yield the product A -pregnatriene-16a, 17a-diol-3,20-dione 16a,17a-sulfite.

EXAMPLE 19 1611,] 70:,21-Triyhdroxy-6-Dehydr0pr0gester0ne 1604,] 7a- Sulfite 21 -Acetate EXAMPLE 20 6-D ehydro-l 6a,] 7OL-D ihydroxy progesterone 16ot,17ot Sulfate Treatment of the product of Example 17, in accordance with the procedure of Example 7, yields the oxidation product 6-deyhdro-16a,l7a-dihydroxyprogesterone 16a,17u-sulfate.

EXAMPLE 21 A -Pregnatriene-1 6 a,] 7a-Diol-3,20-Dione 1 6a,] 7ot-Slilfate The product of Example 20 is enzymatically dehydrogenated with Bacterium cyclooxydans in accordance with the procedure outlined in Example 1 of US. Patent No. 2,822,318 to yield the product A '-pregnatriene-16a, l7a-diol-3,20-dione l6u,17a-sulfate.

EXAMPLE 22 6-Methyl-6-Dehydro-16al 7a-Dihydr0xy progesterone 1 6 0a,] 7 a-S ulfite A solution of 145 mg. of 6a-methyl-16a,17u-dihydroxyprogesterone l6oc,17ot-S1Jlllt6 and 300 mg. of chloranil in a mixture of 7.5 ml. of ethyl acetate and 1.5 ml. of acetic acid is heated under reflux for 42 hours. The reaction mixture is Worked up as described in Example 17. Evaporation of the ethyl acetate extract in vacuo yields a residue which is dissolved in ml. of benzene and chromatographed on 4.5 g. of neutral alumina. Elution with benzene (125 ml.) furnishes about 89 mg. of crystalline material which after recrystallization from acetone-hexane has the following properties: M.P. about 221222; [oz] +l66 (c., .85 in chlf.);

N25,; 286 m (e=16,400) 241 m (=7,400);

V 6.00, 6.14, 6.25, 6.34, and 838 Analysis.Calcd for C I-1 0 8 (404.44) :C, 65.32; H, 6.98; S, 7.93. Found: C, 65.70; H, 7.11; S, 7.22.

EXAMPLE 23 618-Methyl-16a,1 7a-Dihydroxy progesterone 16a,17a-Sulfite To a solution of 190 mg. of Gfi-methyIpregnane-Sa, 16u,l7a-triol-3,20-dione (prepared as described in my copending application Serial No. 764,495 of October 1, 1958) in 5 ml. of dry pyridine is added at 0 0.5 ml. of thionyl chloride. After 7 /2 minutes at 0 ice water is added and the resulting crystalline precipitate filtered and washed well with water. Ice water is added and the resulting mixture extracted with chloroform. The chloroform extract is washed with dilute sulfuric acid, Water, dilute sodium bicarbonate and again With water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting crystalline residue is dissolved in 5 ml. of chloroform and 30 ml. of benzene and chromatographed on 3 g. of neutral alumina. Elution of the column with mixtures of benzene and chloroform, 5:1 (50 ml.), 3:1 (50 ml.) and 2:1 (501111.) furnishes about 125 mg. of crude material which after two crystallizations from chloroform-methanol furnishes pure 6B-methyl-16a,17adihydroxyprogesterone 16a,17m-sulfite of the following y g. of osmium tetroxide in 45 ml. of benzene.

t1mes with water,

n. 239 11 0 are properties: M.P. about 281-283"; [M SH-163 (c., .82 in chlf.); M51; 234 m (e 12,800); k533i? 5.80, 6.00, 6.22, and 8.37

Analysis.Calcd for C H O S (406.46):C, 64.99; H, 7.44. Found: C, 64.98; H, 7.52.

EXAMPLE 24 Treatment of the product of Example 23 in accordance with the microbiological dehydrogenation procedure outlined in Example 1 of US. Patent No. 2,822,318, furnishes the product 6,8-methyl-l6u,l7a-dihydroxy-1-dehydroprogesterone 16a,17a-sulfite.

EXAMPLE 25 6a-Methyl-1 6 0a,] 7a-Dihydroxy progesterone I 1605,] 7 a-Sulfite (A) Preparation of 6u-methyl-16a,17a-dihydr0xypr0gesterone.-To a solution of 3.69 g. of 6a-methyl-16- dehydroprogesterone dissolved in 30 ml. of benzene and 3.6 ml. of dry pyridine is added in the dark, dropwise, with stirring over a period of 2 hours, a solution of 3 The resulting mixture is stirred in the dark for an additional 3% hours, after which 75 ml. of benzene, 138 ml. of methanol, 204 ml. of water, 21.3 g. of sodium sulfite, and 21.3 g. of potassium bicarbonate is added and the mixture shaken for 18 hours. 250 ml. of chloroform is then added and the resulting suspension shaken for an additional /2 hour, filtered and the precipitate washed 3 times with ml. portions of hot chloroform. After separation of the layers, the organic layer is Washed 3 dried over sodium sulfate and the solvents removed in vacuo. The resulting residue (about 4 g.) on crystallization from acetone affords about 3.72 g. of 6a-methyl-l6a,l7u-dihydroxyprogesterone, M.P. about 220-226 C. After recrystallization from acetone the pure glycol is obtained with the following properties: M.P. about 224-226 C; [u] +68 (c., .99 in chlf.);

Nuiol 2.95, 5.90, 6.02, 625p; A233; 2.40 ma (e=16,500)

Analysis.Calcd for C H O (360): C, 73.30; H, 8.95. Found: C, 73.44; H, 8.98.

(B) Preparation of 6a-methyl-16u,17a-dihydr0xy-. progesterone a,]7ot-sulfite.6u-methyl-16a,17a-dihydroxyprogesterone (100 mg.) is reacted with thionyl chlo ride (.4 ml.) in pyridine (3 ml.) exactly as described in Example 1. The crude sulfite ester obtained after evaporation of the chloroform extract is dissolved in 2 ml. of chloroform and 10 ml. of benzene and chromatographed on 2.5 g. of neutral alumina. Elution of the column with a mixture of two parts of chloroform and ten parts of benzene yields about 116 mg. of crude crystalline material, which after recrystallization from acetone-hexane gives pure 6a-methyl-16a,17a-dihydroxyprogesterone 16u,17u-sulfite having the following properties: M.P. about 202-204" and about 221-223 (polymorphic modifications); [a]; +187 (c., 1.10 in chlf.);

5.86, 6.00, 6.25 and 8.39

Analysis.-Calcd for C H O S: C, 64.99; H, 7.44; S, 7.89. Found: C, 64.97; H, 7.61; S, 7.84.

EXAMPLE 26 6 a-M ethy l-] 6 0a,] 7a-D ihydroxy progesterone 160e,] 7a-Sulfate 6u-methyl-16a,17a-dihydroxyprogesterone (200 mg.) is reacted with 0.2 ml of sulfuryl chloride in 5 ml. of pyridine as described in Example 15. The residue from the chloroform extract (270 mg.) is. dissolved in 4 ml. of benzene and 4 ml. of hexane and chromatographed on 5 g. of neutral alumina. Elution with a mixture of one part of benzene and one part of hexane furnishes is about 60 mg. of crystalline material which is first re- EXAMPLE 27 16,170:,21-Trihydroxypr0gester0ne 16a,] 7 a-Sul fate The product of Example 9 is treated with an aqueous solution of potassium carbonate at room temperature. Separation of the precipitate from the reaction mixture yields the product 16a,17a,2l-trihydroxyprogesterone 16a, Una-sulfate.

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound represented by the following general formula:

wherein the 1,2 and 6,7 positions are connected by a linkage selected from the group consisting of a single and a double bond; Q is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen, lower alkyl, fluoro and chloro; n is an integer selected from the group consisting of one and two; and Z is a member selected from the group consisting of hydrogen, halogen, hydroxy and the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms.

2. 16a,l7a-dihydroxyprogesterone 1606,17Ct-S111fit6.

3. 16B-methy1-16a,l7a-dihydroxyprogesterone 1604,1704- sulfite.

4. 16a,17a-dihydroxyprogesterone 16a,17oL-S1llfa't8.

5. 6oz fluoro 16a,17a-dihydroxyprogesterone 16a,17otsulfite.

6. 6e -fiuoro-16a,17a-dihydroxyprogesterone 160:,17asulfite.

7. 6-dehydro-l6a,17a-dihydroxyprogesterone 16a,17ocsulfite.

8. 6 methyl 6 dehydro l6a,l7a dihydroxyprogesterone 16a,17 z-sulfite.

9. methyl-16oz,17a-dihydroxyprogesterone 16a,l7asulfite.

10. 6ot-methyl-16a,l7a-dihydroxyprogesterone 16a,17usulfite.

11. A process which comprises treating a 16a,17a-dihydroxyprogesterone with a member selected from the group consisting of sulfuryl chloride and thionyl chloride in an organic nitrogen base at a temperature of about 0 C. and below, and separating the 16uc,17oc-CyC1iC ester thus formed.

12. A process for the preparation of the 16,17-cyclic esters of 16,8 methyl-16a,17u-dihydroxyprogesterones which comprises treating a A -16-methyl-pregnadiene- 3,6-01-20-0116 with a lower alkylene glycol in the presence of an acid, oxidizing the thus formed A -16-methylpregnadiene-3,8-ol-20-one-20-lower alkylene ketal to the corresponding A -3-one, treating the A *-3-one first with osmium tetroXide and then a reducing agent, treating the resulting 16-methyl-16a,17a-dihydroxyprogesterone ZO-ketal with a member selected from the group consisting of thionyl chloride and sulfuryl chloride in an organic nitrogen base at a temperature of about 0 C. and below to form the corresponding 16a,17a-cyclic ester, and converting said cyclic ester by acid hydrolysis to a 16fl-methyl-16cx, 17ct-dihydroxyprogesterone 16ot,17a-CYCliC ester.

13. A5116 16-methylpregnadiene-3B-ol-20-one 20-ethylene ketal.

14. A -16-methylpregnadiene-3,20-dione ZO-ethyleneketal.

15. methyl 16a,l7a-dihydroxyprogesterone 20- ethylene-ketal.

16. 16 3 methyl-16a,l7u-dihydroxyprogesterone 16oz, 17a-sulfite ZO-ethylene-ketal.

17. A process which comprises treating a 6,8-halopregnane-5a,16a,l7a-triol-3,20-dione, wherein the halogen is a member selected from the group consisting of fluoro and chloro, with a member selected from the group consisting of thionyl chloride and sulfuryl chloride in an organic nitrogen base at a temperature of about 0 C. and below, and recovering the corresponding 16a, 17a-cyclic ester of 16/3-halo-16a,l7a-dihydroxyprogesterone thus formed.

18. A process which comprises treating a 6,8-rnethy1pregnames-5a,16m,l7a-triol-3,20-dione with a member selected from the group consisting of thionyl chloride and sulfuryl chloride in an organic nitrogen base at a temperature of about 0 C. and below, and recovering the corresponding 16a,17oc-CyCliC ester of 6B-methyl-16a,l7a-dihydroxyprogesterone thus formed.

References Cited in the file of this patent Cooley et al.: J. Chem. Soc. (London), 1955, pp. 4373-6.

Mills etaL: J.A.C.S., 81, 1264-5 (1959).

Allen et al.: J.A.C.S., 81, 496879 (1959).

Noller: Chemistry of Organic Compounds (1957), W. B. Saunders, Co., Philadelphia, Pa., page 101.

Fieser et al.: Steroids (1959), Reinhold Pub. Corp, New York, N.Y., page 786.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,049,540 August 14, 1962 Josef Fried It is hereby certified that error appears in the above numbered pa ent requiring correction and that the said Letters Patent should read a: corrected below.

Column 1, line 55, for "ester" read esters colur 10, line 73, for "miscrobiologically" read microbiologic: column 12, line 42, for "62511)" read 6.25p column 14, line 43, for "l6,6haloread 6,8-ha1o- Signed and sealed this 25th day of December 1962.

(SEAL) Attest:

ERNEST w. SWIDER DAVID LADD Attesting Office! Commissioner of Pater 

1. A COMPOUND REPRESENTED BY THE FOLLOWING GENERAL FORMULA: 